Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
  • C07F9/6574—Esters of oxyacids of phosphorus
  • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
  • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
  • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/094—Esters of phosphoric acids with arylalkanols
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/06—Phosphorus compounds without P—C bonds
  • C07F9/08—Esters of oxyacids of phosphorus
  • C07F9/09—Esters of phosphoric acids
  • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to 2-amino-propanol derivatives, process for their production and pharmaceutical compositions containing them.
• m is 1 , 2 or 3;
• X is O or a direct bond;
• R T is H; Ci-s alkyl optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C 2 - 6 alkenyl; C 2 - 6 alkynyl; or phenyl optionally substituted by OH;
• R 5 is H or C h alky! optionally substituted by 1 , 2 or 3 halogen atoms, and R 6 is
• each of R 3 and R 4 independently, is H, C h alky! optionally substituted by halogen, or acyl, and R is C ⁇ 3 - 2 oalkyl which may optionally have in the chain an oxygen atom and which may optionally be substituted by nitro, halogen, amino, hydroxy or carboxy; or a residue of formula (a)
• R 7 is H, C 1-4 alkyl or C ⁇ alkoxy
• R 8 is substituted C 1-20 alkanoyl, phenylCi. 14 alkyl wherein the d. ⁇ 4 alkyl is optionally substituted by halogen or OH, cycloalkyld. 1 alkoxy or phenyld-ualkoxy wherein the cycloalkyl or phenyl ring is optionally substituted by halogen, C h alky! and/or C ⁇ alkoxy, phenylC 1-14 alkoxyC M alkyl, phenoxyd.
• R 8 is C 1-14 alkoxy when R 1 is C 1-4 alkyl, C 2 ⁇ alkenyl or d- ⁇ alkynyl, in free form or in salt form.
• Halogen is F, Cl, Br or I.
• Alkyl or alkoxy may be straight or branched chain.
• Cycloalkyl is preferably C 3 . 10 cycloalkyl, more preferably C 3-8 cycloalkyl and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Acyl is optionally substituted alkanoyl or aroyl, in which alkanoyl is a straight- or branched chain alkanoyl having 1 to 20 carbon atoms, and is e.g. formyl, acetyl, propionyl, butanoyl isobutyryl, pentanoyl or hexanoyl.
• alkanoyl is a straight- or branched chain alkanoyl having 1 to 20 carbon atoms, and is e.g. formyl, acetyl, propionyl, butanoyl isobutyryl, pentanoyl or hexanoyl.
• aroyl include e.g. benzoyl.
• C ⁇ . 2 oalkanoyl is preferably C 2-14 alkanoyl and may optionally be substituted, e.g. by phenyl or cycloalkyl, e.g. cyclohex
• substituted alkanoyl examples include e.g. benzoyl, phenylacetyl, phenylpropionyl, phenylbutanoyl, cyclohexylacetyl, cyclohexylpropionyl, cyclohexylbutanoyl or cyclohexylbutanoyl.
• phenylC 1-1 alkyl or phenyld. 1 alkoxy the d. 14 alkyl or C 1-1 alkoxy moiety preferably contains 1 to 10 carbon atoms.
• Ri When Ri is substituted d- ⁇ alkyl, it may be C 1-6 alkyl substituted by OH, preferably at the terminal position, or C h alky! substituted by 1 , 2 or 3 substituents selected from acyl, halogen, cycloalkyl, phenyl and hydroxy-phenylene.
• m is 1 or 2, preferably 1.
• Ri is d- ⁇ alkyl optionally substituted by OH; C 2 ⁇ alkenyl; or C 2 - 6 alkynyl.
• R 3 and R 4 are H.
• R 5 and R 6 are H.
• R is a residue of formula (a).
• R 7 is H.
• R 7 is C 1- alkoxy, e.g. methoxy.
• R 8 is substituted d. 20 alkanoyl, phenylC ⁇ . 14 alkyl wherein the C 1-14 alkyl is substituted by halogen or OH, cycloalkyld. 14 alkoxy, or phenyld. 14 alkoxy wherein the phenyl ring is optionally substituted by halogen, C h alky! and/or C 1-4 alkoxy.
• Ri is C 2 - 6 alkenyl or C 2 ⁇ alkynyl and R is a residue of formula (a) wherein R 8 is Ci- ⁇ alkoxy. 11. R is a residue of formula (a) wherein R 8 is C 4 _ 3 alkoxy.
• R 8 is in meta or para position to -(CH 2 ) 2 - -, preferably in para.
• R 7 is in ortho to R 8 .
• Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts; when R 5 or R 6 is H, R may also be present in salt form, e.g. an ammonium salt or salts with metals such as sodium, potassium, calcium, zinc or magnesium, or a mixture thereof.
• Compounds of formula I and their salts in hydrate or solvate forms are also part of the invention.
• the compounds of formula I When the compounds of formula I have one or more asymetric centers in the molecule, various optical isomers are obtained.
• the present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof.
• the central carbon atom bearing R and ⁇ may have the R or S configuration.
• the compounds of formula I include geometric isomers, the present invention embraces cis-compounds, trans- compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms or unsaturated bonds as mentioned above.
• Preferred compounds of formula I are e.g. the monophosphate of 2-amino-2-tetradecyl-1 ,3- propanediol, phosphoric acid mono- ⁇ 2-amino-2-hydroxymethyl-4-[4-(5-phenyl-pentanoyl)- phenyl]-butyl ⁇ ester and phosphoric acid mono- ⁇ 2-amino-2-hydroxymethyl-4-[4-(7-phenyl- heptanoyl)-phenyl]-butyl ⁇ ester.
• the present invention also includes a process for the preparation of a compound of formula I which process comprises removing the hydrolysable groups present in R' 2 and the amino protecting group R' 4 in a compound of formula II
• each of R' 5 and R' 6> independently, is a hydrolysable group
• R' is an amino protecting group, and, where required, converting the compounds of formula I obtained in free form into the desired salt form, or vice versa.
• R' 5 and R' 6 are identical and have the significance of e.g. phenyl or benzyl or form together a cyclic system such as in 1 ,5-dihydro-2,4,3-benzodioxaphosphepin.
• suitable amino protecting groups as R' are e.g. as disclosed in "Protective Groups in Organic Synthesis" T.W. Greene, J.Wiley & Sons NY, 2 nd ed., chapter 7, 1991, and references therein, e.g. acyl, e.g. tert.-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl, trifluoroacetyl, trimethylsilylethanesulfonyl and the like.
• the removal of the amino protecting group and/or of R' 5 or R' 6 groups in the compounds wherein X is O may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in a basic medium, for example using a hydroxide such as barium hydroxide. It may also be performed by hydrogenolysis, e.g. in the presence of Pearlman's catalyst, e.g. as disclosed in J.Org.Chem., 1998, 63, 2375-2377.
• the removal of the amino protecting group and/or of R' 5 or R' 6 groups in the compounds wherein X is a direct bond may be conveniently performed according to methods known in the art, e.g. by hydrolysis, e.g. in an acidic medium, by hydrogenolysis or e.g. as disclosed by G. Osapay et al. Tetrahedron 43 (13), 2977-2983.
• a phosphorylating agent e.g. a phosphorochloridate, e.g.diphenylchlorophosphate or dibenzylchlorophosphate, cyanoethylphosphate, a phosphoramidate such as N-phenyl phosphoramidate, 3-(diethylamino)-1 ,5-dihydro-2,4,3-benzodioxaphosphepin and the like.
• reaction may be carried out according to methods known in the art, e.g. as disclosed in
• R 1t R 3, R' 4 and m are as defined above, and
• Y is a leaving group, e.g. Br, with e.g. diethyl phosphite under reducing conditions, e.g. in the presence of NaH.
• the reaction may be performed in accordance with methods known in the art, e.g. as disclosed by G. Osapay et al in supra.
• the OH and amino protection may be performed simultaneously by reacting the free aminoalcohol or aminodiol of formula Ilia or lllb in order to obtain a cyclic residue formed by the amino group and the alcohol group, e.g. oxazolidin-2-one, e.g. by reaction with Cbo-CI, Boc-anhydride or phosgene under basic conditions.
• n 2, 3 or 4
• R 1x is H; optionally substituted by OH, acyl, halogen, cycloalkyl, phenyl or hydroxy-phenylene; C 2 ⁇ alkenyl; d- ⁇ alkynyl; or phenyl optionally substituted by OH;
• R 2 x is H, d ⁇ alkyl or acyl each of R 3x and R 4x , independently, is H, d ⁇ alkyl optionally substituted by halogen or acyl,
• R 5x is H, C ⁇ alkyl or C ⁇ alkoxy, and R 6x is C 1 . 20 alkanoyl substituted by cycloalkyl; cycloalkyld. 14 alkoxy wherein the cycloalkyl ring is optionally substituted by halogen, d ⁇ alkyl and/or C 1-4 alkoxy; phenyld- ⁇ alkoxy wherein the phenyl ring is optionally substituted by halogen, d ⁇ alkyl and/or C 1-4 alkoxy,
• R 6x being also C 4-14 alkoxy when R 1x is C 3 - 4 alkyl substituted by OH, or pentyloxy or hexyloxy when R 1x is C h alky!, provided that R 6x is other than phenyl-butylenoxy when either R 5x is H or R 1x is methyl, in free form or in salt form, are novel and form part of the invention.
• C 4-1 alkoxy as R 6x is preferably C ⁇ oalkoxy.
• Compounds of formula X may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts.
• inorganic acids such as hydrochloride, hydrobromide or sulfate
• organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts.
• Compounds of formula X and their salts in hydrate or solvate forms form also part of the invention.
• the compounds of formula X When the compounds of formula X have one or more asymetric centers in the molecule, various optical isomers are obtained.
• the present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof.
• the central carbon atom in formula X may have the R or S configuration.
• the compounds of formula X include geometric isomers, the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms.
• Compounds of formula X may be prepared in accordance with methods known in the art, e.g. as disclosed in EP-A1- 0 778 263 or EP-A1-0 627 406, e.g by removing either a hydroxy-protecting group present in R 1x or in R 2 ⁇ in a compound of formula X comprising a hydroxy-protecting group in R 1x or in R 2 ,,, or an amino-protecting group present in R x or R 3x in a compound of formula X comprising an amino-protecting group in R 4x or R 3x , e.g. as disclosed in Examples 17 to 27. If one of R 3x or R 4x is an amino-protecting group, then the other is preferably H.
• R' 6x is C 4-14 alkyl, cycloalkylC 1-14 alkyl or phenyld. 1 alkyl wherein the cycloalkyl or phenyl ring is optionally substituted as stated for R 6x .
• Compounds of formula X wherein R 6x is d. 20 alkanoyl may be prepared starting with an aldehyde as disclosed in EP-A1-1 002 792 and followed by a Grignard reaction to introduce the desired R 6x group.
• the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter, e.g. in example 6.
• step a) Compound of step a) (1.1 g, 2 mmol) is dissolved in dichloromethane (100 ml) and then treated with TEA (0.42 ml; 3 mmol) and diphenylphosporyl chloride (0.45 ml, 2.2 mmol). After 16 hours at RT the reaction medium is extracted with 0.5N HCI and the organic phase is separated, dried and concentrated. The crude compound is purified on silica gel using cyclohexane/ethyl acetate (3/1) as mobile phase.
• step i) The endproduct of step i) (60 mg; 0.11 mmol) is treated with glacial acetic acid (1 ml) and concentrated HCI (0.1 ml) for 30 minutes at RT. After diluting with water (10 ml) the reaction mixture is freeze dried. Pure title compound is obtained without any further purification.
• Triethylamine (5.3 ml) is added to a solution of the endproduct of step a) (8.1 g; 27 mmol) in dry dichloromethane (150 ml).
• the reaction mixture is cooled to 0° C and after addition of methanesulphonyl chloride (2.5 ml; 32.4 mmol) the reaction is kept at 0° C for 30 minutes. After quenching with water the organic layer is dried over MgS0 and evaporated to yield a colourless oil.
• the residue is dissolved in dry acetone (200 ml) and Nal (5.3 g; 35.1 mmol) is added and the reaction mixture is kept at RT for 14 hours and then refluxed for 4 hours.
• step c) To a solution of the endproduct of step c) (2.5 g; 5.0 mmol) in dry THF (10 ml) at -78°C there is added n-butyllithium (3.4 ml; 5.5 mmol; 1.6M in n-hexane). After 30 minutes at - 78°C methyliodide (0.37 ml; 6 mmol) dissolved in dry THF (15 ml) is added tropwise over a period of 10 minutes. The reaction mixture is allowed to warm up to RT and it is kept at RT for 3 hours.
• N-Boc-(R)-2-Amino-2-ethyl-4-[3-methoxy-4-(4-phenyl-butoxy)-phenyl]-butan- 1-ol (0.23 g; 0.5 mmol) in THF (5 ml) is added N,N-diethyl-1,5-dihydro-2,4,3- benzodioxaphosphepin-3-amine (0.24 g; 1 mmol) and tetrazole (0.11 g; 1.5 mmol).
• RT H 2 O 2 (30% in water; 0.58 ml) is added and the mixture is kept at RT for further two hours.
• step h) The endproduct of step h) (82 mg; 0.13 mmol) is dissolved in ethanol/ethyl acetate (30 ml 2/1) and hydrogenated with Pd/C 10% as catalyst under normal pressure for two hours. After filtering and evaporation the title compound is isolated as a colorless oil. MS (ES) 538,3 [M+Hf
• Example 8 Phosphoric acid mono- ⁇ (R)-2-amino-2-methyl-4-[4-(3-phenyl-propoxy)- phenyl]-butyl ⁇ ester
• step f) The endproduct of step f) below is treated with glacial acetic acid (1 ml) and concentrated HCI (0.1 ml) for 30 minutes at RT. After diluting with water (10 ml) the reaction mixture is freeze dried. Pure title compound is obtained without any further purification.
• Example 10 Phosphoric acid mono-((R)-2-amino-4- ⁇ 4-[3-(4-methoxy-phenyl)-propoxy]- phenyl ⁇ -2-methyl-butyl) ester
• Example 12 Phosphoric acid mono- ⁇ (R)-2-amino-2-methyl-4-[4-(5-phenyl-pentyloxy)- phenyl]-butyl ⁇ ester
• Example 13 Phosphoric acid mono- ⁇ (R)-2-amino-2-methyl-4-[4-(4-phenyl-butoxy)- phenyl]-butyl ⁇ ester
• CibCHzO 1.90 (m, 2H, CCH 2 ), 2.59 (m, 2H, CH 2 Ph), 2.67 (d, 2H, HCCCHz), 3.18 (CCH),
• Example 16a Phosphoric acid mono-r R)-2-amino-4-(4-hexyloxv-phenvl)-2-methvl- butyl] ester
• Example 16b Phosphoric acid mono-[(R)-2-amino-2-ethyl-4-(4-heptyloxy-phenyl)- butyl] ester
• step iii) (50 mg; 0.14 mmol) is treated with glacial acetic acid (0.5 ml) and concentrated HCI (0.05 ml) at RT for 20 minutes.
• the reaction mixture is diluted with ethyl acetate (2 ml) and then treated with diethylether (20 ml) to afford a white precipitate.
• the precipitate is filtered off and washed 2 times with diethylether and dried.
• Example 27 1 -r4-(3-Amino-4-hvdroxv-3-hvdroxvmethvl-butvl )-phenvl 1-5-cvclohexvl- pentan-1-one
• the compounds of formula I and the compounds of formula X, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
• compounds of the invention exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
• the compounds of the invention have binding affinity to individual human S1P receptors as determined in following assays:
• proteins are cloned, and equal amounts of 4 cDNAs for the EDG receptor, G r ⁇ , G r ⁇ and G r ⁇ are mixed and used to transfect monolayers of HEK293 cells using the calcium phosphate precipitate method (M. Wigler et al., Cell. 1977,;11;223 and DS. Im et al., Mol. Pharmacol. 2000;57;753). Briefly, a DNA mixture containing 25 ⁇ g of DNA and 0.25 M CaCI is added to HEPES-buffered 2 mM Na 2 HPO 4 .
• Subconfluent monolayers of HEK293 cells are poisoned with 25 mM chloroquine, and the DNA precipitate is then applied to the cells. After 4 h, the monolayers are washed with phosphate-buffered saline and refed media (90% 1:1 Dulbecco's modified essential media (DMEM):F-12 + 10% fetal bovine serum). The cells are harvested 48-72 h after addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5 MgCI 2 , 1 EDTA, pH 7.4) containing 10% sucrose on ice, and disrupted using a Dounce homogenizer.
• HME buffer in mM: 20 HEPES, 5 MgCI 2 , 1 EDTA, pH 7.4
• Ligand-mediated GTP ⁇ S binding to G-proteins is measured in GTP binding buffer (in mM: 50 HEPES, 100 NaCI, 10 MgCI 2 , pH 7.5) using 25 ⁇ g of a membrane preparation from transiently transfected HEK293 cells. Ligand is added to membranes in the presence of 10 ⁇ M GDP and 0.1 nM [ 35 S]GTP ⁇ S (1200 Ci/mmol) and incubated at 30 °C for
• the compounds of the invention have binding affinities to S1P receptors in the sub-microM range.
• a compound of the invention or the vehicle is administered orally by gavage to rats.
• Tail blood for hematological monitoring is obtained on day -1 to give the baseline individual values, and at 2, 6, 24, 48 and 72 hours after drug application.
• the compounds of the invention deplete peripheral blood lymphocytes when administered at a dose of 0.03 to 3 mg/kg.
• Compound of Examples 1 , 2, 6f , 20, 22, 23, 26 depletes peripheral blood lymphocytes by more than 50% 24 hours after administration of a dose of 0.4; 0.6; 0.5; 0.1; 0.05; 0.2; and 0.3 mg/kg, respectively.
• the compounds of the invention are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
• rheumatoid arthritis systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g.
• inflammatory bowel disease Crohn's disease or ulcerative colitis
• intrinsic asthma inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, others, cancer, e.g.
• T cell lymphomas or T cell leukemias infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
• infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
• cell, tissue or solid organ transplants include e.g. pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus.
• Compounds of the invention do not show the negative chronotropic effects as does sphingosine-1 phosphate.
• the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight.
• An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
• Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
• the compounds of the invention may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
• Pharmaceutical compositions comprising a compound of the invention in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
• the compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
• Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
• the present invention further provides:
• a method for preventing or treating disorders or diseases mediated by lymphocytes, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof;
• a method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof;
• a compound of the invention in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 or 1.2 above.
• a pharmaceutical composition e.g. for use in any of the methods as in 1.1 or 1.2 above comprising a compound of the invention in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefor. 4. A compound of the invention or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition for use in any of the method as in 1.1 or 1.2 above.
• the compounds of the invention may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent.
• the compounds of the invention may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTOR inhibitor, e.g.
• rapamycin 40-O-(2- hydroxyethyl)-rapamycin, CCI779 or ABT578; an ascomycin having immunosuppressive properties, e.g. ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15- deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40.
• CD45, CD58, CD80, CD86 or their ligands other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y ; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil.
• a chemotherapeutic agent e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or
• the co-administered immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
• the present invention provides in a yet further aspect:
• a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of the invention and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
• a second drug substance e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
• a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug.
• the kit may comprise instructions for its administration.
• co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
• pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
• fixed combination means that the active ingredients, e.g. a compound of the invention and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• non-fixed combination means that the active ingredients, e.g. a compound of the invention and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
• cocktail therapy e.g. the administration of 3 or more active ingredients.
• a preferred compound of the invention is the compound of Example 1.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Immunology (AREA)
• Diabetes (AREA)
• Neurology (AREA)
• Pulmonology (AREA)
• Neurosurgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Biomedical Technology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Heart & Thoracic Surgery (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Endocrinology (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Rheumatology (AREA)
• Hematology (AREA)
• Dermatology (AREA)
• Transplantation (AREA)
• Pain & Pain Management (AREA)
• Virology (AREA)
• Ophthalmology & Optometry (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)

Priority Applications (13)

Applications Claiming Priority (6)

Publications (2)

Family

ID=27256123

Family Applications (1)

Country Status (18)

Cited By (44)

Families Citing this family (5)

Family Cites Families (6)

• 2002
  • 2002-03-26 AT AT02727484T patent/ATE314383T1/de active
  • 2002-03-26 MX MXPA03008755A patent/MXPA03008755A/es unknown
  • 2002-03-26 PL PL02367348A patent/PL367348A1/xx not_active Application Discontinuation
  • 2002-03-26 CA CA002442178A patent/CA2442178A1/en not_active Abandoned
  • 2002-03-26 CN CNA028068378A patent/CN1620461A/zh active Pending
  • 2002-03-26 CZ CZ20032560A patent/CZ20032560A3/cs unknown
  • 2002-03-26 DK DK02727484T patent/DK1377593T3/da active
  • 2002-03-26 EP EP02727484A patent/EP1377593B1/en not_active Expired - Lifetime
  • 2002-03-26 SK SK1194-2003A patent/SK11942003A3/sk unknown
  • 2002-03-26 WO PCT/EP2002/003389 patent/WO2002076995A2/en not_active Ceased
  • 2002-03-26 ES ES02727484T patent/ES2254675T3/es not_active Expired - Lifetime
  • 2002-03-26 DE DE60208355T patent/DE60208355T2/de not_active Expired - Lifetime
  • 2002-03-26 IL IL15777302A patent/IL157773A0/xx unknown
  • 2002-03-26 KR KR10-2003-7012474A patent/KR20030093279A/ko not_active Ceased
  • 2002-03-26 JP JP2002576253A patent/JP4012823B2/ja not_active Expired - Fee Related
  • 2002-03-26 BR BR0208365-5A patent/BR0208365A/pt not_active Application Discontinuation
  • 2002-03-26 US US10/472,127 patent/US7326801B2/en not_active Expired - Fee Related
• 2003
  • 2003-09-25 NO NO20034291A patent/NO20034291L/no not_active Application Discontinuation

Also Published As

Similar Documents

Legal Events